POS0244 ASSOCIATION OF PROTEINASE 3 GENE (PRTN3) Val119Ile POLYMORPHISM (SNP rs351111) WITH RISK OF RELAPSE AMONG HOMOZYGOUS PATIENTS WITH PR3 ANCA-ASSOCIATED VASCULITIS
Authors: M. Casal Moura, Z. Deng, S. Brooks, W. Tew, A. Hummel, F. Fervenza, C. Kallenberg, C. Langford, P. A. Merkel, P. A. Monach, P. Seo, R. Spiera, W. St. Clair, J. H. Stone, M. Prunotto, P. Grayson, U. Specks
Journal: Annals of the Rheumatic Diseases (2022)

Background The frequency of the proteinase 3 gene (PRTN3) polymorphisms in patients with ANCA-associated vasculitis (AAV) is not well characterized. We hypothesize that PRTN3 gene polymorphisms induce allosteric changes in PR3 conformation which may alter its interaction with ligands and PR3-ANCA during inflammation with potential implications for disease presentation and clinical outcomes. Objectives To analyze the association of PRTN3 Val119Ile polymorphism (SNP rs351111) with risk of relapse risk among homozygous patients with PR3 ANCA-associated vasculitis. Methods DNA variant calling for SNP rs351111 (chr.19:844020, c.355G&gt;A) in PRTN3 gene assessed the allelic frequency in patients with PR3-AAV included in the Rituximab versus Cyclophosphamide (RAVE) trial. This was followed by RNA-seq variant calling to characterize the mRNA expression. We compared clinical presentation and outcomes between patients homozygous for PR3-Ile 119 or PR3-Val 119 . Results Serum samples for DNA calling were available in 188 of the 197 patients with AAV in the RAVE cohort. 75 PR3-AAV patients had the allelic variant: 13 patients were homozygous for PR3-Ile 119 and 62 patients were heterozygous PR3-Val 119 Ile with an allele frequency threshold of 29.3 – 55.1% of reads (Figure 1A and 1B). RNA-seq was available for 89 patients and the mRNA corresponding to the allelic variant was found in 35 PR3-AAV patients: 13 patients were homozygous for PR3-Ile 119 and 22 patients were heterozygous PR3-Val 119 Ile with an allele frequency threshold of 11.1 – 62.8% of reads (Figure 1A and 1C). The agreement between the DNA calling results and the mRNA expression of the 86 patients that overlapped was 100%. We found an additional homozygous patient for PR3-Val 119 in which blood was not available for DNA calling. We compared the clinical presentation and outcomes of 74 patients with PR3-AAV: 13 homozygous for PR3-Ile 119 and 51 homozygous for PR3-Val 119 (Table 1). The frequency of severe flares at 18 months in homozygous PR3-Ile 119 was ≥ 2x higher when compared with homozygous PR3-Val 119 (46.2% vs. 19.6%, p=0.048). We found no differences in clinical presentation. Figure 1. RAVE trial population distribution according to the zygosity status for PRTN3 gene (PR3 and MPO-ANCA patients) and DNA or RNA variant calling (panel A). Allelic frequency for rs351111, chr.19:844020 (c.355G&gt;A) in PRTN3 among patients with AAV (PR3 and MPO-ANCA) in the DNA (panel B) and RNA (panel C) variant calling. Table 1. Outcomes of patients with PR3-ANCA according with PRTN3 zygosity. PR3-ANCA (n=64) Homozygous PR3-Val 119 (n=51) HomozygousPR3-Ile 119 (n=13) p-value Remission, n (%) 45 (88.2) 13 (100) 0.194 Complete remission, n (%) 36 (70.6) 10 (76.9) 0.650 Any flare 18 months, n (%) 30 (58.8) 7 (53.8) 0.746 Severe Relapse* 18 months, n (%) 10 (19.6) 6 (46.2) 0.048 * Relapse was considered “Severe” if Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) &gt; 3 or one major item as per the RAVE trial definition. Abbreviations: ANCA - anti-neutrophil cytoplasmic antibody; Ile – isoleucine; n- number; PR3 - proteinase 3; Val - valine. Conclusion In patients with PR3-AAV the presence of PRTN3 Val 119 Ile polymorphism was associated with higher frequency of severe relapse. Further studies are necessary to understand the association of this observation with the risk of severe relapse. References [1]Stone JH et al N Engl J Med 2010; 363:221-232 Disclosure of Interests None declared